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Indium-Catalyzed HeteroarylЦHeteroaryl Bond Formation through Nucleophilic Aromatic Substitution.

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Angewandte
Chemie
DOI: 10.1002/ange.201005750
Indium Catalysis
Indium-Catalyzed Heteroaryl–Heteroaryl Bond Formation through
Nucleophilic Aromatic Substitution**
Teruhisa Tsuchimoto,* Mami Iwabuchi, Yuta Nagase, Kenji Oki, and Hiroshi Takahashi
Heteroaromatic molecules bearing heteroaryl–heteroaryl
bonds are an important class of building blocks found in a
variety of areas; for example, optoelectronic materials,[1]
liquid crystals,[2] biological compounds,[3] and ligands for
asymmetric catalysis.[4] Over the past 35 years, transitionmetal-catalyzed cross-coupling reactions have been chiefly
responsible for making (hetero)aryl–(hetero)aryl bonds.[5] On
the other hand, nucleophilic aromatic substitution (SNAr) has
actually been studied to construct such biaryl linkages since
the 1940s.[6] However, aromatic compounds, which are
intrinsically electron-rich, are in general unreactive toward
nucleophilic substitution.[7] Therefore, two aryl substrates
with entirely opposite electronic demands must be arranged
to realize biaryl synthesis by the SNAr reaction. Thus,
electron-rich aryl nucleophiles with highly electropositive
metals (e.g. Li+, Mg2+, Zn2+) and/or electron-poor aryl
electrophiles with one or more strong electron-withdrawing
groups (EWGs; e.g. CF3, NO2, CN, CO2R) have each been the
aryl substrate of choice.[8] More than a stoichiometric amount
of promoter is also often necessary.[8c,p,q] These requisites may
have limited the widespread applicability of biaryl synthesis
based on SNAr. We envisioned that catalytic biaryl synthesis
by SNAr independent of such activated aryl substrates would
be an attractive alternative to the transition-metal-catalyzed
cross-coupling strategy. Herein, we report the first example of
a catalytic heteroaryl–heteroaryl bond-forming reaction
based on SNAr without using both the heteroarylmetal
nucleophile and heteroaryl electrophile substituted with
EWGs.
Initially, we studied the effect of changing the leaving
group X in thiophene derivatives 2 (acting as electrophiles) in
the indium-catalyzed reaction of 2-methylindole (1 a; acting
as a nucleophile; Table 1). On treatment of 1 a and 2 bearing
various halides (X = I, Br, Cl) with 2 mol % of In(OTf)3 (Tf =
SO2CF3) in 1,4-dioxane at 85 8C for 5 h, no desired reaction
occurred. Neither the nitro nor cyano groups, which often
behave as leaving groups in SNAr reactions, worked at all. In
[*] Prof. Dr. T. Tsuchimoto, M. Iwabuchi, Y. Nagase, K. Oki,
H. Takahashi
Department of Applied Chemistry
School of Science and Technology
Meiji University, Higashimita, Tama-ku, Kawasaki, 214-8571 (Japan)
Fax: (+ 81) 44-934-7228
E-mail: tsuchimo@isc.meiji.ac.jp
Homepage: http://www.isc.meiji.ac.jp/ ~ tsuchi/
[**] Financial support by a Grant-in-Aid for Scientific Research
(no. 19750083) from the Ministry of Education, Culture, Sports,
Science and Technology is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005750.
Angew. Chem. 2011, 123, 1411 –1415
Table 1: Effect of changing X.[a]
X
Conv. of 2 [%][b]
Yield of 3 a [%][c]
I
Br
Cl
NO2
CN
OMe (2 a)
OAc
OTf
3
2
5
9
5
99
24
> 99
<1
<1
<1
<1
<1
35
<1
<1
[a] Reaction conditions: 1 a (0.325 mmol), 2 (0.250 mmol), In(OTf)3
(5.00 mmol), 1,4-dioxane (1.0 mL), 85 8C, 5 h. [b] Determined by GC
analysis. [c] Determined by 1H NMR spectroscopy. Tf = SO2CF3.
sharp contrast, 2 a, having a methoxy group, reacted with 1 a
to give thienylindole 3 a in 35 % yield, while the related
oxygen-based leaving groups such as OAc and OTf gave
disappointing results, despite their better leaving ability
compared with OMe.[9] Next, we tested other solvents in the
reaction of 1 a with 2 a (Table 2). The ethereal solvent DME,
which is similar to 1,4-dioxane, was efficient while other
solvents made the reaction sluggish. After thorough investigations on a co-solvent for 1,4-dioxane and DME, we found
that the yield of 3 a was markedly increased to 80 % in a mixed
solvent system, consisting of 1,4-dioxane and toluene (25:1).
Other indium salts as well as metal triflates were less effective
(Table 3). No reaction occurred without a catalyst. With
In(OTf)3 as a catalyst, the fine-tuning of the solvent volume
finally raised the yield up to 86 %. The results in Table 3 might
Table 2: Effect of solvents.[a]
Solvent
Conv. of 2 a [%][b]
Yield of 3 a [%][c]
1,4-dioxane
DME
CH3CH2CN
ClCH2CH2Cl
PhCl
PhCH3
1,4-dioxane/PhCH3[d]
DME/PhCH3[d]
99
71
44
36
10
12
99
95
35
53
25
21
2
8
80
73
[a] Reaction conditions: 1 a (0.325 mmol), 2 a (0.250 mmol), In(OTf)3
(5.00 mmol), solvent (1.0 mL), 85 8C, 5 h. [b] Determined by GC analysis.
[c] Determined by 1H NMR spectroscopy. [d] The solvent ratio is 25:1
(1.0 mL:40 mL). DME = dimethoxyethane.
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zuschriften
Table 3: Effect of Lewis acids.[a]
Lewis acid
Conv. of 2 a [%][b]
Yield of 3 a [%][c]
In(OTf)3
In(ONf)3
In(NTf2)3
InCl3
Cu(OTf)2
AgOTf
Bi(OTf)3
Sc(OTf)3
Y(OTf)3
Yb(OTf)3
none
In(OTf)3[d]
99
> 99
38
<1
81
99
98
45
13
24
<1
> 99
80
74
18
<1
59
73
73
18
4
8
<1
86
[a] Reaction conditions: 1 a (0.325 mmol), 2 a (0.250 mmol), Lewis acid
(5.00 mmol), 1,4-dioxane/PhCH3 (1.0 mL:40 mL), 85 8C, 5 h. [b] Determined by GC analysis. [c] Determined by 1H NMR spectroscopy. [d] Used
1,4-dioxane/PhCH3 [0.5 mL:40 mL (12.5:1)]. Nf = SO2C4F9.
indicate that Lewis acids consisting of a rather soft metal and
strong electron-withdrawing ligands tend to be favorable as
catalysts, owing to the lower catalytic activity of the hard
Lewis acids with strong electron-withdrawing ligands such as
Sc-, Y-, and Yb(OTf)3 and of the soft Lewis acid with weaker
electron-withdrawing ones like InCl3.[10] Notably, 3 a is
accessible in one step from commercially available 1 a and
2 a; this is important because presynthesis of heteroarylmetal
nucleophiles and heteroaryl electrophiles substituted with
EWGs is not desired.
We next examined the substrate scope. As shown in
Scheme 1, indoles 1 with Me, nBu, OMe, Br, Ph, and/or pMeOC6H4 groups displaced the OMe group from 2 a to afford
3 b–3 j, where 1,2,3-triarylindole 3 j, having a fully extended pconjugation system, is included. The OMe groups on indole
substrates remained intact, thus showing remarkable chemoselectivities (see 3 b, 3 c, 3 i, 3 j, and 3 l). 3-Methoxythiophene
(2 b) also reacted with 1 to give 3 k and 3 l. Even more
electron-rich 2,5-dimethoxythiophene (2 c; as compared with
2 a) also participated in this reaction (Scheme 2). The
interesting aspect is that the appropriate choice of reaction
conditions enables exclusive access to either the single or
double substitution of 2 c, thus leading to 3 m or 3 n,
respectively.[11] The single substitution even proceeded at
room temperature in a higher yield. Potentially useful quaterheteroaryl 3 o was obtained directly by the double substitution of 2 d with 1 b [Eq. (1)].
Scheme 1. Indium-catalyzed SNAr reaction of various indoles 1 with 2 a
or 2 b. Yields of isolated 3 a–3 l are shown here. Further details on
reaction conditions for each reaction are provided in the Supporting
Information. [a] In(ONf)3 (10 mol %) instead of In(OTf)3 was used.
Scheme 2. Indium-catalyzed SNAr reaction of 1 a with 2 c.
The strategy is also applicable to the synthesis of other biand ter-heteroaryls. While the In(OTf)3-catalyzed reaction of
1 a with 2 e bearing the OMe group delivered no desired
product, replacing 2 e with 2 f having the OTf group and
replacing In(OTf)3 with Bi(OTf)3 altered the result drastically, giving pyridylindole 3 p in 67 % yield [Eq. (2)]. 3Acetoxyindole (2 g) is an excellent electrophile in terms of the
reaction efficiency, but unfortunately not with respect to the
regiochemistry [Eq. (3)].[12] We then found that pyrroles 1 c
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2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2011, 123, 1411 –1415
Angewandte
Chemie
appears to be the most plausible, as well demonstrated in the
SNAr reaction via p complexes between transition metals and
arenes.[14] Heteroaryl rings with higher p-electron density are
thought to be more favorable for complexation with an
electrophilic InIII atom,[15] thereby they are activated more
efficiently. Accordingly, the findings that 2 c with two
methoxy groups is much more reactive than 2 a and that
thiophenes 2 with electron-withdrawing groups (halides, NO2,
CN, OTf) are inactive also support the validity of the reaction
proceeding via complex A (Scheme 1, Scheme 2, and
Table 1).
Taking the above observations into consideration, possible mechanisms are depicted in Scheme 4, which shows the
reaction of HetAr–D 1 and 2 a.[16] Although it is still unclear at
and 1 d also work well as nucleophiles [Eqs. (4) and (5)]. As
Equation (5) shows, the substitution of the OMe group in 3 m,
which was prepared as shown in Scheme 2, with 1,2-dimethylpyrrole (1 d) provided ter-heteroaryl 3 s that is connected
regularly in the order of pyrrole, thiophene, and indole rings.
In this case, In(ONf)3 was a superior catalyst to its triflate
salt.[13]
A possible route for this reaction is depicted in Scheme 3,
which exemplifies the reaction of 2 a with HetAr–H 1. At least
three coordination modes of 2 a to InX3 (In; complexes A, B,
and C) appear to be possible as triggers of this reaction. To
gain insight into the details, we performed the reaction of
deuterium-labeled indole [D]-1 e (95 % [D]) with 2 a under
the standard conditions [Eq. (6)]. The reaction gave [D]-3 g
and [D]-3 g’ incorporating a deuterium atom on the C3’- or
C5’-poition of the thiophene ring with 72 % total deuterium
content, thus suggesting that a carbon indium bond trapped
by D+ is formed during the reaction. Therefore, complex A in
which the carbon atoms of 2 a coordinate directly to the In
Scheme 3. A possible reaction route through complexes A, B, or C.
Angew. Chem. 2011, 123, 1411 –1415
Scheme 4. Possible reaction mechanisms.
present which one of either path a or path b is in operation,
allylindium-type intermediates 4 and/or 4’ would be formed
first by the nucleophilic attack of 1 to complex A,[17] in which
the In moiety can be regarded as a tentative EWG to make 2 a
electrophilic enough to react. Subsequent transfer of the
deuterium atom from the HetAr+–D to the a site and/or g site
in the allylindium unit would give 5 and/or 5’.[18] The
elimination of MeOH(D) for the re-aromatization would
lead to [D]-3 and [D]-3’. The 23 % loss of the D atom (95 %
deuteration of [D]-1 e to total 72 % deuteration of [D]-3 g and
[D]-3 g’) should be ascribed to the final step in which both
MeOH and MeOD would be eliminated.
In summary, for the first time, we have achieved catalytic
heteroaryl–heteroaryl bond formation based on the SNAr
reaction using two easily available heteroaryl substrates that
require no activating groups. We also considered the reason
why heteroaryl electrophiles 2 without EWGs work well,
based on the mechanistic studies on which complex A is the
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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plausible coordination mode. In general, transition-metalcatalyzed cross-coupling using indolyl- and pyrrolylmetal
compounds is impractical since their presynthesis requires
multiple steps.[19] Our strategy will thus be highly useful in
such cases.
[7]
Experimental Section
[8]
[6]
Synthesis of 3 a (Scheme 1): In(OTf)3 (2.8 mg, 5.0 mmol) was added to
a 20 mL Schlenk tube, which was heated at 150 8C in vacuo for 2 h and
then filled with argon. To this were added 1,4-dioxane (0.5 mL) and
toluene (40 mL), and the resulting solution was stirred at RT for
10 min before 2-methylindole (42.6 mg, 0.325 mmol) and 2-methoxythiophene (28.5 mg, 0.250 mmol) were added successively. After
stirring at 85 8C for 5 h, a saturated NaHCO3 aqueous solution
(0.5 mL) was added and the aqueous phase was extracted with EtOAc
(5 mL 3). The combined organic layer was washed with brine and
then dried over anhydrous Na2SO4. Filtration and evaporation of the
solvent and subsequent column chromatography on silica gel (nhexane/EtOAc = 6:1) gave 2-methyl-3-(thiophen-2-yl)-1H-indole
(3 a; 45.6 mg, 82 %).
Received: September 14, 2010
Published online: December 30, 2010
.
Keywords: aromatic substitution · heteroarenes · heterocycles ·
indium · Lewis acids
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2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2011, 123, 1411 –1415
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Chemie
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[17] As one reviewer suggested, there is also a possibility of a
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the adjacent oxygen and sulfur atoms, and then nucleophilic
attack of HetAr–D 1 to the cation.
Angew. Chem. 2011, 123, 1411 –1415
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2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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